Spinal cord injury (SCI) causes loss of spinal cord cells, damage to ascending and descending axonal tracts and loss of myelination, resulting in paralysis. After SCI, axonal regeneration is prevented by the lack of matrix that supports growth through production of important growth and morphogenic factors (Harel and Strittmatter 2006; Lu and Tuszynski 2007). Successful treatment of SCI will include approaches that aid in the regeneration of damaged axons and/or in the replacement of oligodendrocytes to improve myelination.
Stem cell therapy has been envisioned as a treatment that may serve to prevent and/or reverse SCI by replacing damaged or lost spinal cord cells, delivering factors conducive to spinal cord repair, and providing a physical scaffold for instructing and enabling axon regrowth. However, at present, the technology to successfully direct stem cell differentiation into the appropriate or desired cell type in vivo is lacking. Specifically, research studying stem cells in the context of treating SCI has shown that transplanted neural stem cells (NSC) do not differentiate into the appropriate cell types for neuron regeneration, such as oligodendrocytes and neurons. NSCs instead differentiate into primarily astrocytes in vivo, thereby limiting functional recovery (Enzmann et al. 2006).
One reason functional recovery from SCI is limited is because the microenvironment of the adult spinal cord lacks the necessary biological cues for proper differentiation of NSCs into neurons and oligodendrocytes. The spinal cord microenvironment instead favors astrogliogenesis, (the growth of astrocytes), thereby adding to the astroglial scar, which is believed to be an impermeable barrier to recovering, outgrowing axons (Silver and Miller 2004). It has been demonstrated in vitro that exogenous factors are needed to direct NSC differentiation toward the cell types useful for SCI treatment, including oligodendrocytes and neurons (Cattaneo 1990; Gage 2000).
Achieving delivery of soluble growth factors to the site of SCI is a challenging problem. If injected once, soluble factors flow away quickly from the injury site after injection. Furthermore, long-term pumps, which have been used in other applications to deliver soluble factors, are difficult to use in SCI patients, as the human spinal cord moves significantly as a result of respiratory variations and the pulse, thus catheters tend to migrate. A need exists for a method that can provide sustained delivery of important growth factors to the site of injury over a prolonged period of time.
Sonic hedgehog (Shh) is a multifunctional factor that acts as a morphogen early in spinal cord development, when different cell types are established (Jessell 2000), and as a guidance factor for the commissural axons at later developmental stages (Charron et al. 2003). Specifically, Shh influences the glial choice by inducing oligodendrocyte differentiation and inhibiting the astrocyte lineage (Tekki-Kessaris et al. 2001; Sussman et al. 2002; Agius et al. 2004); Shh treatment in vitro results in the enhancement of neurite outgrowth from dorsal root ganglion neurons (So et al. 2006). Direct injection of soluble Shh into the spinal cord at the time of injury results in improved nerve-to-muscle conductivity, although no functional recovery is observed. Functional recovery can be measured in terms of improved motor or sensory function, usually assessed with behavioral tests, such as measuring the ability of mice to walk on a horizontal ladder. The failure to improve function is likely due to rapid clearance of Shh from the central nervous system (CNS) (Bambakidis and Miller 2004).
Spinal cord injuries are not only common, but they are at present difficult to treat, because NSCs do not differentiate on their own into oligodendrocytes and neurons. While some growth factors, such as Shh, are known to drive this differentiation, it has up to now not been known how to harness this beneficial effect in vivo. Thus, there is a longstanding unfulfilled need for effective spinal cord injury treatments, and also, more generally, for treatments useful in the CNS that would provide or result in the delivery of an effective amount of a desired exogenous factor to the spinal cord or nervous system location to facilitate neural cell recovery (e.g. to provide a niche for growth and repair in this environment).